Novel chloro and bromoalkyl carbonates of salicylic acid



United States Patent 3,499,023 NOVEL CHLORO AND BROMOALKYL CARBON- ATES 0F SALICYLIC ACID Joseph V. Swintosky, Perkiomenville, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Aug. 19, 1965, Ser. No. 481,059 Int. Cl. C07c 63/00, 63/14 US. Cl. 260-463 3 Claims ABSTRACT OF THE DISCLOSURE Trichloro and tribromoalkyl carbonates of salicylic acid having analgetic activity. Method of preparation comprises reacting salicylic acid with a chloroformate of the particular chlorinated or brominated lower alkanol in any suitable organic solvent with the desired product separating spontaneously.

This invention relates to new organic compounds having valuable pharmacodynamic properties. More specifically this invention relates to chloro and bromoalkyl carbonates of salicylic acid having the following structural formula:

wherein X is a chlorinated or brominated lower alkyl group. The term lower alkyl is here and elsewhere employed to designate a straight or branched group containing a maximum of four carbon atoms. Preferably the chlorinated and brominated lower alkyl group contain less than four halogen atoms. Most advantageously the lower alkyl group will contain three halogen atoms.

The preferred and most advantageous compounds of this invention are the 2,2,Z-trichloroethylcarbonate of salicylic acid and the corresponding 2,2,2-tribromoethylcarbonate.

The compounds of this invention are particularly useful as analgetics. The novel compounds of this invention are as potent analgetics as aspirin and they are absorbed rapidly giving blood concentrations equivalent to those of aspirin. However, these compounds are particularly advantageous analgetics because they do not cause the gastrointestinal disturbances which is observed following the administration of aspirin. The novel chloro and bromoalkyl carbonates of this invention are therefore effective analgetic agents demonstrating minimal side effects.

The compounds of this invention are prepared by the following synthetic procedure:

The salicylic acid is treated with a chloroformate of the particular chlorinated or brominated lower alkanol. The reaction may be carried out in any suitable organic solvent. The desired product separates spontaneously and is filtered and dried. The desired chloroformate compound may be prepared by treating the appropriate chlorinated as brominated lower alkanol with phosgene according to standard methods known to the art, as for example, Slimowicz et al., J.A.C.S., 71, 1044 (1949).

3,499,023 Patented Mar. 3, 1970 The novel chloro and bromoalkyl carbonates as represented by the above Formula I are advantageously employed in combination with either a liquid or solid nontoxic pharmaceutical carrier. A wide variety of pharmaceutical forms useful for oral ingestion may be employed. Advantageously the preparation may take the form of tablets, capsules, powders, troches or lozenges. When a solid form is employed the pharmaceutical carrier may be, for example, lactose, magnesium stearate, starch, gums such as acacia, terra alba, stearic acid, sorbitol, mannitol, ethyl cellulose or gelatin. The amount of solid carrier will vary widely but preferably is from about 25 mg. to about 1 gm. If a liquid carrier is used the preparation can be in the form of a soft gelatin capsule, placed in an ampule or in a liquid suspension.

The pharmaceutical forms comprising the above compounds of Formula I are administered in dosage units internally, preferably orally. Advantageously equal daily doses are administered to provide a daily dosage regimen which produces analgesic activity.

The following examples will further serve to describe this invention. These examples are not limiting but are illustrative of compounds of this invention and the procedures for their preparation.

EXAMPLE 1 (A) Preparation of 2,2,2-trichloroethyl chloroformate 2,2,2 trichloroethanol (149.5 g., 1.0 mole) is added dropwise with stirring to g. of liquid phosgene in a Dry Ice-trichloroethylene bath, maintaining a temperature of 0 or lower. The mixture is allowed to slowly reach room temperature upon completion of the addition while a calcium chloride protected outlet is employed to permit escape of excess phosgene. The mixture is then aerated and the 2,2,2-trichloroethyl chloroformate purified by distillation at reduced pressure.

(B) Preparation of 2,2,Z-trichloroethylcarbonate of salicylic acid To a solution of 50 gms. of salicylic acid in 250ml. of benzene is added 88 gms. of N,N-dimethylaniline and the solution is cooled. To the cooled solution is added dr0pwise 77 gms. of trichloroethyl chloroformate. The solution is then extracted with dilute hydrochloric acid and the product is crystallized from the benzene and dried to yield the 2,2,2-trichloroethylcarbonate of salicylic acid melting at C.-127 C.

EXAMPLE 2.

Employing the general procedures outlined in parts A and B of the above Example 1 and equivalent amounts of starting material, similar transformations give the following results:

(A) Starting material.2,2,2 tribromoethanol and salicylic acid.

Pr0duct.-2,2,2 tribromoethylcarbonate of salicylic acid.

(B) Starting material.-2 methyl 2 chloro lpropanol and salicylic acid.

Product.2-methyl 2 chloropropylcarbonate of salicylic acid.

(C) Starting material.-3 bromo-Z-butanol and salicylic acid.

Pr0duct.3-bromo-2-butylcarbonate of salicylic acid.

(D) Starting material.-3,3,3 trichloropropanol and salicylic acid.

Product.--3,3,3 trichloropropylcarbonate of salicylic acid.

(E) Starting material.Trichloromethyldimethylcarbinol and salicylic acid.

Product.--2-trichloromethyl-Z-propylcarbonate of salicylic acid.

3,499,023 3 v s 4 What is claimed is: Z. 2,2,2-trichloroethylcarbonate of salicylic acid. 1. A compound of the formula: 3. 2,2,Z-tribromoethylcarbonate of salicylic acid.

' References Cited O 5 UNITED STATES PATENTS H 639,174 12/1899 Hofmann 260-463 E BERNARD HELFIN, Primary Examiner 10 L. DE CRESCENTE, Assistant Examiner wherein X is a trichlorinated or tribrominated lower alkyl US. Cl. X.R. group comprising up to four carbon atoms. -9 

